Nimodipine Reduces Dysfunction and Demyelination in Models of Multiple Sclerosis.

OBJECTIVE: Treatment of relapses in multiple sclerosis (MS) has not advanced beyond steroid use, which reduces acute loss of function, but has little effect on residual disability. Acute loss of function in an MS model (experimental autoimmune encephalomyelitis [EAE]) is partly due to central nervous system (CNS) hypoxia, and function can promptly improve upon breathing oxygen. Here, we investigate the cause of the hypoxia and whether it is due to a deficit in oxygen supply arising from impaired vascular perfusion. We also explore whether the CNS-selective vasodilating agent, nimodipine, may provide a therapy to restore function, and protect from demyelination in 2 MS models. METHODS: A variety of methods have been used to measure basic cardiovascular physiology, spinal oxygenation, mitochondrial function, and tissue perfusion in EAE. RESULTS: We report that the tissue hypoxia in EAE is associated with a profound hypoperfusion of the inflamed spinal cord. Treatment with nimodipine restores spinal oxygenation and can rapidly improve function. Nimodipine therapy also reduces demyelination in both EAE and a model of the early MS lesion. INTERPRETATION: Loss of function in EAE, and demyelination in EAE, and the model of the early MS lesion, seem to be due, at least in part, to tissue hypoxia due to local spinal hypoperfusion. Therapy to improve blood flow not only protects neurological function but also reduces demyelination. We conclude that nimodipine could be repurposed to offer substantial clinical benefit in MS. ANN NEUROL 2020 ANN NEUROL 2020;88:123-136.

Drosophila oogenesis as a bio-marker responding to EMF sources.

The model biological organisms Drosophila melanogaster and Drosophila virilis have been utilized to assess effects on apoptotic cell death of follicles during oogenesis and reproductive capacity (fecundity) decline. A total of 280 different experiments were performed using newly emerged flies exposed for short time daily for 3-7 d to various EMF sources including: GSM 900/1800 MHz mobile phone, 1880-1900 MHz DECT wireless base, DECT wireless handset, mobile phone-DECT handset combination, 2.44 GHz wireless network (Wi-Fi), 2.44 GHz blue tooth, 92.8 MHz FM generator, 27.15 MHz baby monitor, 900 MHz CW RF generator and microwave oven's 2.44 GHz RF and magnetic field components. Mobile phone was used as a reference exposure system for evaluating factors considered very important in dosimetry extending our published work with D. melanogaster to the insect D. virilis. Distance from the emitting source, the exposure duration and the repeatability were examined. All EMF sources used created statistically significant effects regarding fecundity and cell death-apoptosis induction, even at very low intensity levels (0.3 V/m blue tooth radiation), well below ICNIRP's guidelines, suggesting that Drosophila oogenesis system is suitable to be used as a biomarker for exploring potential EMF bioactivity. Also, there is no linear cumulative effect when increasing the duration of exposure or using one EMF source after the other (i.e. mobile phone and DECT handset) at the specific conditions used. The role of the average versus the peak E-field values as measured by spectrum analyzers on the final effects is discussed.

Mitochondrial dysfunction is an important cause of neurological deficits in an inflammatory model of multiple sclerosis.

Neuroinflammation can cause major neurological dysfunction, without demyelination, in both multiple sclerosis (MS) and a mouse model of the disease (experimental autoimmune encephalomyelitis; EAE), but the mechanisms remain obscure. Confocal in vivo imaging of the mouse EAE spinal cord reveals that impaired neurological function correlates with the depolarisation of both the axonal mitochondria and the axons themselves. Indeed, the depolarisation parallels the expression of neurological deficit at the onset of disease, and during relapse, improving during remission in conjunction with the deficit. Mitochondrial dysfunction, fragmentation and impaired trafficking were most severe in regions of extravasated perivascular inflammatory cells. The dysfunction at disease onset was accompanied by increased expression of the rate-limiting glycolytic enzyme phosphofructokinase-2 in activated astrocytes, and by selective reduction in spinal mitochondrial complex I activity. The metabolic changes preceded any demyelination or axonal degeneration. We conclude that mitochondrial dysfunction is a major cause of reversible neurological deficits in neuroinflammatory disease, such as MS.